PROJECT SUMMARY Benzo(a)pyrene [B(a)P], an ubiquitous environmental toxicant, is a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds and has been implicated in the causation of colorectal cancer (CRC). Additionally, consumption of red meat and saturated fats, toxicants such as PAHs has also been implicated as one of the risk factors for sporadic colon cancer. Our preliminary studies not only show that B(a)P causes colon cancer, but that administration of Western diet to B(a)P-treated Polyposis in Rat Coli (PIRC) rats increases the development of adenomas in the colon. Our proposed studies will test the hypothesis that Western diet exacerbates B(a)P-initiated colon carcinogenesis through altered biotransformation and DNA damage. We will test our hypothesis in adult male transgenic PIRC rats with the following specific aims: 1. Characterize and validate the PIRC rat as a model to study how Western diet potentiates B(a)P-induced colon carcinogenesis; 2. Determine diet-induced alteration of B(a)P biotransformation enzyme activities, expression, and metabolite disposition in the PIRC rat; and 3. Assess the contribution of regular and Western diet in the formation and persistence of B(a)P-DNA adducts and oxidative DNA damage in the PIRC rat. This project will provide new and interesting information with regard to the contribution of Western diet towards increasing the development of colorectal polyps. The goals of this application are also to provide the intellectual environment and resources for the applicant to enrich herself in various approaches in her chosen area of research via a training plan that incorporates: 1) Mentored research activity; 2) Active participation & presentation in meetings, seminars and journal clubs; 3) Interaction with visiting scientists; 4) Periodic evaluation of applicant's research progress through individual development plan; 5) Publishing research findings in peer-reviewed journals; and 6) Participation in career development activities. It is expected that by the end of the training period, the applicant will be successful in her chosen research endeavor and contribute to the diversity of the research workforce, a goal of the Ruth L. Kirschstein predoctoral fellowship. Relevance of this project to human health Colorectal cancer contributes to significant mortalities in the United States, with 50,000 deaths per year. Consumption of fatty foods contaminated with B(a)P was implicated as a causative factor. One-third of adults and 17% of adolescents in the United State are obese. Obese people have a higher risk for colon cancer due to the excess energy intake from Western diet. We plan to study the progression of CRC, using a rat model that mirrors the human CRC scenario. We also propose to use Western diet, (>58% fat), as an accelerator of CRC. Our findings will be of use to determining the mechanistic effects of diet on B(a)P-caused initiation, promotion and progression of CRC.